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2,5-Methano- and 2,5-Ethano-Tetrahydrobenzazepine Derivatives And Use Thereof To Block Reuptake Of Norepinephrine, Dopamine, and Serotonin

a technology of ethanotetrahydrobenzazepine and ethanotetrahydrobenzazepine, which is applied in the field of compounds, can solve the problems of unresponsive subset of the population, slow onset of action, and common side effects of anticholinergic and sedative drugs,

Inactive Publication Date: 2012-02-23
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although TCAs are very effective antidepressants, cardiovascular, anticholinergic and sedative side effects are common due to the interaction of TCAs with muscarinic, histaminic and adrenergic receptors.
There are several known difficulties with the SSRI class of therapeutics, including the slow onset of action, unwanted side effects, and the existence of a significant subset of the population that is not responsive to SSRI therapy.

Method used

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  • 2,5-Methano- and 2,5-Ethano-Tetrahydrobenzazepine Derivatives And Use Thereof To Block Reuptake Of Norepinephrine, Dopamine, and Serotonin
  • 2,5-Methano- and 2,5-Ethano-Tetrahydrobenzazepine Derivatives And Use Thereof To Block Reuptake Of Norepinephrine, Dopamine, and Serotonin
  • 2,5-Methano- and 2,5-Ethano-Tetrahydrobenzazepine Derivatives And Use Thereof To Block Reuptake Of Norepinephrine, Dopamine, and Serotonin

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of rac-5-(4-chlorophenyl)-8-methoxy-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine, L-tartrate Salt

[0248]

[0249]Step A: To pyrrolidin-3-ol (3.4 g, 39 mmol) in methanol (150 mL) was added 3-methoxybenzaldehyde (6.4 g, 47 mmol) and iodine (0.40 g, 32 mmol). After stirring for 5 h, the reaction mixture was cooled to 0° C. and sodium borohydride (2.9 g, 78 mmol) was added portionwise. The reaction mixture was warmed to ambient temperature and stirred overnight. Water (10 mL) was added and most of the tetrahydrofuran was removed in vacuo. Additional water (25 mL) was added and the aqueous layer was extracted with methylene chloride (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride / methanol / ammonium hydroxide) to provide 1-(3-methoxybenzyl)pyrrolidin-3-ol (2.0 g, 25%) as a yellow oil: 1H NMR (DMSO-d6, 300 MHz) δ 7.21 (dd, J=8.1, 8.1 Hz, 1H), 6....

example 2

Preparation of rac-5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ol, L-tartrate Salt

[0254]

[0255]Step A: A mixture of 5-(4-chlorophenyl)-8-methoxy-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine (100 mg, 0.33 mmol) from Step D of Example 1 in 48% hydrobromic acid in water (2 mL) and acetic acid (2 mL) was heated to 135° C. After 4 h, the reaction mixture was cooled to ambient temperature, brought to ca. pH 7-8 with 1 N sodium hydroxide and saturated sodium bicarbonate and extracted with ethyl acetate (2×). The combined organics were washed with brine and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride / methanol / ammonium hydroxide) to provide 5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ol (67 mg, 70%) as a white solid.

[0256]Step B: To the benzazepinol (25 mg, 0.087 mmol) from Step A above in methanol (1.5 mL) and acetonitrile (4 mL) was added L-tartaric acid (13...

example 3

Preparation of (+)- and (−)-8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepine, L-tartrate Salts

[0257]

[0258]Step A: To a suspension of 5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ol (270 mg, 0.94 mmol) from Step A of Example 2 in methylene chloride (10 mL), at −20° C., was added pyridine (0.084 mL, 1.0 mmol) and triflic anhydride (0.018 mL, 1.0 mmol). After 1 h, additional pyridine (0.020 mL, 0.25 mmol) and triflic anhydride (0.031 mL, 0.18 mmol) were added. After 0.5 h at 0° C., additional pyridine (0.020 mL, 0.25 mmol) and triflic anhydride (0.031 mL, 0.18 mmol) were added. After 1.25 h, the reaction mixture was diluted with methylene chloride (20 mL) and saturated sodium bicarbonate (10 mL) was added. The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 5-(4-chlorophenyl)-2,5-methano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl t...

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Abstract

The compounds of the present invention are represented by the following 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives having formula (I):where the carbon atom designated * is in the R or S configuration when n is 1 and the substituents X and R1-R7 are as defined herein.

Description

[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61 / 374,470, filed Aug. 17, 2011, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to compounds, compositions, and methods for the treatment of various neurological and psychological disorders, and the use of the compounds in combination therapy. In particular, the present invention relates to such compounds, compositions, and methods, where the compounds are novel 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives.BACKGROUND OF THE INVENTION[0003]Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and / or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking reuptake of the neurotransmitter(s) from ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55C07D519/00A61P25/00A61P25/06A61P25/18A61P25/24A61P25/16A61P25/14C07D487/08A61P25/22
CPCC07D519/00C07D453/00A61P25/00A61P25/06A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24
Inventor GUZZO, PETER R.LIU, SHUANGRYAN, KRISTEN N.MOLINO, BRUCE F.DEORAZIO, RUSSELLOLSON, RICHARD E.MACOR, JOHN E.
Owner ALBANY MOLECULAR RESEARCH INC
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